WO2013110975A1 - Improved nitazoxanide composition and preparation method thereof - Google Patents

Description

 COMPOSITION OF N IT AZOX AN IDA IMPROVED

 AND PROCESS TO PREPARE

Field of the Invention

The present invention relates to pharmaceutical compositions for the oral administration of nitazoxanide in granules for suspension and to the process for preparing them. The compositions of the present invention are useful for the treatment of intestinal parasitic infections and have an improved gastrointestinal adverse effect profile compared to existing formulations. The compositions of the present invention present fractions with different release profile of the active principle: (a) an immediate release fraction, (b) a fraction of pH-dependent release that begins to release between pH 5.0 and pH 7.5. Optionally, the fraction that releases pH-dependently, can be formed by two fractions, a fraction that starts to release between pH 5.0 and pH 6.0 and another fraction that starts to release between pH 6.5 and pH 7.5. The compositions of the present invention can be administered in a single daily dose or even allow the entire treatment to be administered as a single dose.

Background of the Invention

Nitazoxanide is a 5-nitrothiazole with antiparasitic and antibacterial activity with broad spectrum of action. Its chemical formula is 2-acetyloxy-N- (5-nitro-2-thiazolyl) benzamide and has the following structure:

The procedure for the synthesis of nitazoxanide and the use of this compound were originally disclosed by Rossignol in US Patent 3,950,351. US Pat. No. 5,387,598 discloses formulations of nitazoxanide suitable for the treatment of intestinal infections by improved parasites by the use of surfactant excipients and starch. Patent US 5,968,961 discloses formulations of nitazoxanide with optimum particle size to achieve the therapeutic effect and reduce the adverse effects. US Pat. No. 6,117,894 discloses improved nitazoxanide formulations in terms of stability by the use of acidifying excipients. Patent application US 20100209505 discloses nitazoxanide compositions in bilayer tablets where one layer is immediate release and the other layer is controlled release designed specifically for the treatment of chronic viral hepatitis C.

Nitazoxanide is currently approved in several countries for the treatment of infections caused by parasites in two pharmaceutical forms: immediate release tablets and powder for immediate release suspension. These formulations require the administration of 1 shot every 12 hours. Depending on the age of the patient, the following dose scheme and method of administration are used: Age Dosage Total daily dose

 1 to 3 years 100 mg every 12 hours 200 mg

 4 to 11 years 200 mg every 12 hours 400 mg

 12 to 15 years 300 mg every 12 hours 600 mg

 16 years or more 500 mg every 12 hours 1000 mg

The main adverse effects of nitazoxanide are gastrointestinal, being the most frequent: abdominal pain, diarrhea, nausea and vomiting. These effects increase as the dose is increased. The gastrointestinal adverse effects of the known formulations of nitazoxanide are very frequent and cause a significant percentage of patients not to complete the treatment. The partial compliance of the treatment generates the reappearance of the infection and increases the probability of generating resistance to the drug.

Therefore, there is a need to have an improved formulation of nitazoxanide for the treatment of parasitic infections that allows better tolerance and better treatment compliance.

It should be noted that the controlled release tablet composition disclosed by Rossignol in the patent application US 20100209505 is not adequate to solve the problem raised for several reasons. The formulation developed by Rossignol is specifically designed for the treatment of chronic viral hepatitis C (systemic treatment that requires high plasma levels of nitazoxanide). In the aforementioned patent application, the inventor uses high viscosity polymers such as hydroxypropyl methylcellulose (Methocel) or hydroxypropyl cellulose (Klucel) which, when hydrated and swollen, remain in the stomach longer (gastroretention phenomenon). In this way they manage to release the active principle gradually in the zone of greater absorption of nitazoxanide (in the stomach and first portion of the intestine). The controlled-release tablets revealed by Rossignol do not achieve a sufficient reduction of gastrointestinal adverse effects. As reported in the aforementioned patent application for the 675 mg dose, the most common adverse effects were: Diarrhea 33%, Nausea 25% and Abdominal Pain 17%.

On the other hand, the controlled-release tablets described by Rossignol containing 675 mg of nitazoxanide are very bulky, weighing more than 1000 mg. This type of tablets is not suitable for pediatric patients or adult patients with swallowing problems due to its large size.

For these reasons, it was planned to find a composition that could overcome these drawbacks, which gave rise to the present invention. In the present invention we design a nitazoxanide composition capable of releasing the active principle in pulses in order to distribute the active principle throughout the intestinal tract and allow a better tolerance. We have achieved that the release of nitazoxanide directed to different regions of the digestive system allows to significantly reduce the adverse effects of the treatment. After multiple tests, it has been found that the composition of the present invention achieves the desired dissolution profile by combining an immediate release fraction and at least one pH-dependent release fraction.

Brief Description of the Figures

Figure 1 shows the in-vitro dissolution profile of the suspension of Example 6

Figure 2 shows the in-vitro dissolution profile of the suspension of Example 8 Detailed description of the invention

The compositions of the present invention combine an immediate release fraction and a pH-dependent release fraction. The immediate release fraction can be formulated as a powder or as immediate release granules. The pH-dependent release fractions are formed by coated granules of particle size less than 850 microns. The pH-dependent release fraction begins to release between pH 5.0 and pH 7.5. Optionally, the fraction that releases pH-dependently, can be formed by two fractions, a fraction that starts to release between pH 5.0 and pH 6.0 and another fraction that starts to release between pH 6.5 and pH 7.5.

The manufacturing process consists of the following stages: 1) production of pH-dependent release granules; 2) preparation of the immediate release fraction, 3) preparation of the mixture of the fractions together with additional excipients to formulate the suspension; and 4) filling the mixture in envelopes or flasks.

1- Elaboration of pH-dependent release granules

The general process consists of two stages. In a first stage the granules are made (uncoated) and then coated with at least one pH-dependent solubility polymer as a means to regulate the release of the active ingredient.

1.A - Granulation

The first step to make coated granules is to make granules of immediate release. The immediate release granules are formed by nitazoxanide and the less a binder excipient. These granules can be formed by the following techniques: (1) conventional wet granulation (eg granulation in high impact mixer-granulator equipment), (2) dry granulation (compaction), (3) granulation by extrusion-spheronization method, or (4) by applying the active principle to an inert nucleus. The preferred method is that of application of active principle on an inert granule since it allows to obtain spherical granules, with a smooth surface, of fine size and with distribution of limited granulometry. These characteristics are important so that, when coating the granules, the desired dissolution profile is obtained systematically.

The general method of application of nitazoxanide on inert nuclei consists of the following steps: in a reactor of adequate capacity add purified water. Add a binder and keep stirring until it is completely dissolved. Then, add the nitazoxanide and continue stirring to generate a dispersion. Optionally, disintegrating and / or stabilizing agents can be added in this step. Atomize the dispersion obtained on the inert nuclei using a fluid bed equipped with a "wurster" insert or tangential rotor. Dry the obtained granules.

The inert core is preferably spherical. It can be composed of sugar, starch, mannitol, xylitol, microcrystalline cellulose and organic acids, such as fumaric acid or tartaric acid. Preferably, inert nuclei of microcrystalline cellulose are used. More preferably, the microcrystalline cellulose cores are spherical and have a size of less than 700 microns, preferably between 150 to 700 microns. Preferably, Celphere CP203 microcrystalline cellulose cores manufactured by Asahi Kasei having a size between 150 and 300 microns are used. The inert nuclei represent between 50% and 80% of the weight of the granule before coat. Preferably, they represent between 60% and 70% of the weight of the granule before coating.

The binder is a soluble polymer selected from hydroxypropyl cellulose (HPC), hypromellose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and vinylpyrrolidone-vinylacetate copolymer. Preferably, PVP K30 is used. The concentration of the binder is generally between 5% and 30% of the weight of the granule before coating. Preferably, it represents between 10% and 20% of the weight of the granule before coating.

The concentration of nitazoxanide in the granule (before coating) is between 10% and 60% of the weight of the granule. Preferably, it represents between 20% and 50% of the weight of the granule before coating.

In case of adding a stabilizing agent it is an acidifier selected from citric, glutamic, succinic, tartaric, adipic, malic, fumaric, ascorbic acid and mixtures thereof. The preferred stabilizer is citric acid, in a preferred concentration is between 0.1% and 1% of the weight of the granule before coating.

In case of adding a disintegrating agent, it is preferable that it be croscarmellose sodium, sodium starch glycolate or crospovidone. The preferred concentration of the superdintegrating agent is between 1% and 10% of the weight of the granule before coating.

1.B Coating

The coating process comprises the following steps:

(a) In a reactor of adequate capacity, prepare a solution or suspension of coating containing at least one polymer of pH-dependent solubility. Optionally, add plasticizers, anti-stick agents and pH regulators.

 (c) Using a fluid bed equipment equipped with a wurster insert, atomize the coating solution or suspension onto the granules obtained in step 1.A

 (d) Once the application is complete, dry the product.

The granules are coated with one or more polymers of pH-dependent solubility chosen from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate and methacrylic acid copolymers. Preferred are methacrylic acid copolymers, alone or in combination. It is possible to adjust the pH from which the membrane is dissolved by combining different polymers. It is also possible to partially neutralize the acid groups of polymers to adjust the pH from which they are dissolved. For this, alkalizing agents such as sodium hydroxide, sodium bicarbonate or others are used.

To make pellets that release from pH 5.5, the preferred polymer is the methacrylic acid-ethylacrylate copolymer. The concentration of polymer with the coated granule varies between 7% and 40%, and preferably, it is between 10% and 25%.

To produce granules that release from pH 7.0, the preferred polymer consists of the mixture of two polymers: (1) copolymer of methacrylic acid - methyl methacrylate and (2) copolymer of methacrylic acid - ethylacrylate. The concentration of polymers in the coated granule varies between 7% and 40% and is preferably between 10% and 25%. The mixture of the polymers can be made in equal parts or by using a greater amount of methacrylic acid-methylmethacrylate copolymer in relation to methacrylic acid-ethylacrylate copolymer, the ratio 75:25 being the preferred one. Examples of plastifling agents include: triacetin, tributyl citrate, triethyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides, medium chain triglycerides, and similar compounds, with the use of medium chain triglycerides being preferred. The plasticizing agent generally represents between 10 and 20% by weight of the coating polymers.

Examples of antiadherents include: talc, glyceryl monostearate and formulated agents such as Plasacryl T20.

2- Preparation of the immediate release fraction

The immediate release fraction of nitazoxanide can be composed of the uncoated granules described in step 1.A, or it can be unpoiled powder.

3- Preparation of the mixture of the fractions and formulation of the suspension

Once the weight of each of the fractions (immediate release and pH-dependent release) that one wishes to dose is determined, perform a simple mixture of said fractions together with the additional excipients used to formulate the suspension. Additional excipients may include: sweeteners, thickeners, pH regulators, preservatives, dyes and flavors or flavorings. In order to avoid segregation of the mixture, it is preferable that the different fractions and the additional excipients employed have a similar particle size.

When mixing the fractions, the immediate release fraction contains between 20% and 50% of the total dose. The fraction that releases pH-dependently contains between 50% and 80% of the total dose. 4- Dosage of the mixture

Once the mixture of the 3 fractions together with the excipients used to formulate the suspension is obtained, said mixture is filled in envelopes or flasks with the following contents of active principle:

4.A Dosage for treatment with one dose per day for 3 days

4.B Dosage for treatment with a single dose

Medición del perfil de disolución in-vitro:

Measurement of the in-vitro dissolution profile:

The dissolution profile of the composition is measured by the following procedure:

 Apparatus: 2 of the USP (Palettes)

 Speed: 100 rpm

 Volume: 1000 mi

 Temperature: 25 ° C or 37 ° C (at 25 ° C there is less degradation of the asset)

 Means of dissolution:

 Stage 1: 60 minutes in 0.1 N hydrochloric acid with 6% cetiltrimeti lamo nio bromuro

 Stage 2: 60 minutes in phosphate buffer pH 5.5 with 6% cetiltrimeti lamo nio bromuro

 Stage 3: 60 minutes in phosphate buffer pH 7.0 with 6% cetiltrimeti lamo nio bromuro

The fraction of immediate release releases as follows:

The fraction of pH-dependent release that releases at pH 5.5 or higher releases as follows:

Time Stage Specification

 1 h Stage 1 (acid pH) <10%

2h Stage 2 (pH 5.5)> 80% The fraction of pH-dependent release that releases at pH 7.0 or higher releases as follows:

The suspensions of the present invention comprising the three fractions, release the active principle in the following manner:

EXAMPLES OF REALIZATION

Example 1

Preparation of a batch of 3 kg of granules of immediate release.

For the preparation of a batch of 3 kg of granules of immediate release, the following materials were used. Material Function Quantity per batch

 (grams)

Nitazoxanide <100μ Active 690.00 (Romark Labs.)

Microcrystalline Cellulose in Spheres, Inert Nucleus 1906.80 USP / NF (Celphere CP203, Asahi Kasei)

Polyvinylpyrrolidone K30, USP / NF Binder 402.50 (Plasdone K29 / 32, ISP Corp.)

Citric acid anhydrous, USP / NF Stabilizer 0.70 (Jungbunzlauer AG)

 Purified water Vehicle 5750.00 mi

 (evaporates

 during the process)

Total 3000.00

Production process: 1 - Preparation dispersion: In a reactor of adequate capacity add the amount of purified water established. Then add the binding agent (Polyvinylpyrrolidine K30) maintaining the agitation until complete dissolution of the same. Once dissolved, add the stabilizing agent (anhydrous citric acid) verifying its complete dissolution. Finally, add the Nitazoxanide maintaining the agitation until obtaining a homogeneous dispersion. 2- Incorporate the microcrystalline cellulose spheres in a fluid bed equipped with a ^" wurster ^" or tangential rotor insert and atomize the dispersion obtained in point 1. 3- Once the application is finished, dry the obtained granules. Example 2

 Preparation of a batch of pH-dependent release granules coated soluble membrane from pH 5.5.

To make the batch the following materials were used:

Processing process: 1) In a reactor of adequate capacity add the amount of purified water established. Then add the regulatory polymer of the release (Eudragit L100-55) maintaining the agitation until obtaining a homogeneous dispersion. Add the sodium hydroxide and then the plasticizer (Triethylcitrate). Finally, talcum is added maintaining the agitation until obtaining a homogeneous dispersion. 2) Incorporate the granules of immediate release of nitazoxanide in a fluid bed equipped with insert ^" wurster ^" to then atomize the dispersion obtained in point 1. 3) Once the application dry the granules obtained.

Percentage composition of granules that begin to release at pH 5.5

Example 3

 Preparation of a batch of pH-dependent release granules coated soluble membrane from pH 7.0

To make the batch the following materials were used: Material Function Quantity per batch

 (grams)

Immediate release granules (from Example 1) 1000.00

Methacrylic acid-methylmethacrylate copolymer Regulating polymer 105.00 (1: 2), USP / NF (Eudragit S100, Evonik) of the release

Methacrylic acid-ethylacrylate copolymer, USP / NF Regulating polymer 35.00 (Eudragit L100-55, Evonik) of the release

Medium chain triglycerides, NF (Miglyol 812, Plastifing Agent 14.00 Sasol)

Talc, USP / NF (Magnesite Refratarios) Non-stick 14.00

Magnesium stearate, USP / NF (Mallinckrodt) Non-stick 14.00

Ethyl alcohol (Fradealco) Vehicle (evaporates 1866.66 mi during the process)

Total 1182.00

Production process: 1) Preparation of the coating solutions to be used: Incorporate the Eudragit L100-55 and the Eudragit S100 into a reactor with the amount of ethanol established, keeping stirring until complete dissolution of the polymers is observed. Then incorporate the plasticizing agent (medium chain triglycerides) and finally add magnesium stearate until a homogeneous dispersion is obtained. 2) Incorporate the granules of immediate release of nitazoxanide in a fluid bed equipped with a ^" wurster ^" insert and atomize the dispersion containing the polymers on the granules. Add talc in step form during the process to reduce adhesion. 3) Once the application is finished, dry the obtained granules.

Percent composition of granules that begin to release at pH 7.0 Nitazoxanide <100μ (Romark Labs.) 19.46%

 Microcrystalline cellulose in spheres, USP / NF (Celphere 53.77%

 CP203, Asahi Kasei)

 Polyvinylpyrrolidone K30, USP / NF (Plasdone K29 / 32, ISP 11.35%

 Corp.)

 Anhydrous citric acid, USP / NF (Jungbunzlauer AG) 0.02%

 Methacrylic acid-methylmethacrylate copolymer (1: 2), 8.87%

 USP / NF (Eudragit S100, Evonik)

 Methacrylic acid-ethyl acrylate copolymer, USP / NF 2.96%

 (Eudragit L100-55, Evonik)

 Medium chain triglycerides, NF (Miglyol 812, Sasol) 1.19%

 Talc, USP / NF (Magnesite Refratarios) 1.19%

 Magnesium Stearate, USP / NF (Mallinckrodt) 1.19%

 Total 100.00%

Example 4

Development of immediate release powder

For the preparation of a batch of 21 kg of the immediate release fraction, the following materials were used:

g%

 Nitazoxanide <100μ (Romark Labs.) 250.00 1.19%

Refined sugar, USP / NF (Ledesma) 20000.00 95.24%

Microcrystalline Cellulose and Carboxymethylcellulose 628.00 2.99% Sodium, USP / NF (Avicel RC-591, FMC)

Yellow Dye (Vidhi Dyestuffs) 2.00 0.01%

Essence of strawberry powder (RBP 100043, Saporiti) 120.00 0.57%

Total 21000.00 100.00%

Production process: In a suitable mixer make the mixture of Avicel RC-591, yellow dye, essence of strawberry powder and half of the sugar. Then incorporate the nitazoxanide and mix again. Finally add the remaining half of the sugar and mix until a homogeneous mixture is obtained.

Example 5

 Preparation of the mixture for suspension containing 2 pulses. 40% immediate release and 60% release at pH 5.5

In a double cone mixer, the following materials were mixed for 15 minutes: 70 grams of granules of Example 2 (pH 5.5) and 750 g of immediate release powder of Example 4. Component Quantity (g) Nitazoxanide contained (g) Amount of active content in each fraction.

 Granules of Example 2 70 13.29 59.8% (pH 5.5)

Release powder 750 8.92 40.2% immediate of Example 4

Total mix 820 22.21 100%

Analytical results:

 Content of nitazoxanide in the mixture: 20 mg / g.

 Dissolution test using 30 g of product (equivalent to 600 mg of nitazoxanide) per glass:

Conclusion: the product meets the desired profile. Example 6

Preparation of the mixture for suspension containing 3 pulses. 35% immediate release, 45% release at pH 5.5 and 20% release at pH 7.0.

In a double cone mixer the following were mixed for 15 minutes materials: 968 grams of granules of Example 2 (pH 5.5), 420 g of granules of Example 3 (pH 7.0) and 12000 g of immediate release powder of Example 4.

Analytical results:

 Content of nitazoxanide in the mixture: 31 mg / g

 Dissolution test using 32.25 g of product (equivalent to 1 g of nitazoxanide) per glass:

Conclusion: the product meets the desired profile. Example 7

 Conditioning in envelopes

 300 sachets were filled containing 32.25 g of suspension mix each sachet (equivalent to 1 g of nitazoxanide).

The formula of each envelope is as follows

Content per envelope (g)

Nitazoxanide <100μ (Romark Labs.) 1, 00

 Refined sugar, USP / NF (Ledesma) 27.52

Microcrystalline cellulose in spheres, USP / NF (Celphere CP203, 1, 77

 Asahi Kasei)

Microcrystalline cellulose and sodium carboxymethylcellulose, USP / NF 0.86

 (Avicel RC-591, FMC)

 Polyvinylpyrrolidone K30, USP / NF (Plasdone K29 / 32, ISP Corp.) 0.37

Copolymer of methacrylic acid-ethylacrylate, USP / NF (Eudragit 0.30

 L100-55, Evonik)

 Essence of strawberry powder (RBP 100043, Saporiti) 0, 16

 Talc, USP / NF (Magnesite Refratarios) 0, 12

Methacrylic acid-methylmethacrylate copolymer (1: 2), USP / NF 0.09

 (Eudragit S100, Evonik)

Triethylcitrate, USP / NF (Vertellus Performance Materials) 0.03

 Magnesium stearate, USP / NF (Mallinckrodt) 0.01

 Medium chain triglycerides, NF (Miglyol 812, Sasol) 0.01

 Yellow Dye (Vidhi Dyestuffs) 0.005

Sodium hydroxide, USP / NF (Merck) 0.004

Anhydrous citric acid, USP / NF (Jungbunzlauer AG) 0.001

Total 32.25 Example 8

 Preparation of the mixture for suspension containing 3 pulses. 29% immediate release, 35% release at pH 5.5 and 36% release at pH 7.0.

In a double cone mixer the following materials were mixed for 15 minutes: 230 grams of granules of Example 2 (pH 5.5), 230 g of granules of Example 3 (pH 7.0) and 3000 g of immediate release powder of Example 4.

Analytical results:

 Content of nitazoxanide in the mixture: 36 mg / g.

Dissolution test using 83.33 g of product (equivalent to 1 g of nitazoxanide) per glass: Time Stage Specification Result

 1 h Stage 1 (acid pH) 25% -55% 30%

 2h Stage 2 (pH 5.5) 55% -85% 67%

 3h Stage 3 (pH 7.0)> 85% 91%

Conclusion: the product meets the desired profile. Conditioning in jars

 Forty bottles containing 83.33 g of suspension mixture per bottle (equivalent to 3 g of nitazoxanide) were filled.

Example 9

In order to assess the tolerance of the composition, a Phase I, cross-over clinical study was conducted in 24 healthy adult volunteers. As the Reference formulation, the volunteers received reconstituted suspension of nitazoxanide (2 g / 100ml). The dose administered after high caloric breakfast was 25 ml of reconstituted suspension containing 500 mg of nitazoxanide and together with the dinner, another 25 ml of reconstituted suspension containing 500 mg of nitazoxanide. In total, 1000 mg of nitazoxanide was administered in 2 doses of 500 mg each, with an interval of 12 hours between them. As a Test formulation, the volunteers received the formulation of Example 7. The dose administered was the content of 1 sachet (32.25 grams of granules for suspension, containing 1000 mg of nitazoxanide) dispersed in 150 ml of water, after high-calorie breakfast. Hospitalization and Monitoring: In the two periods of the study, the volunteers remained hospitalized during the 24 hours following the administration. The pharmacological rest period (washout) between periods was 7 days. After the administration of the formulations, the Adverse Events were recorded and a control at 48h to verify the remission of the same. Results: The following table summarizes the adverse effects observed (all of mild intensity), for each formulation:

Conclusion: The study showed a greater tolerance for the Test formulation.

Claims

A pharmaceutical composition for oral administration of nitazoxanide useful for the treatment of intestinal parasitic infections in the form of suspension granules characterized in that it contains:  (a) an immediate release fraction composed of uncoated granules or non-granular powder of nitazoxanide; Y  (b) a pH-dependent release fraction formed by granules of nitazoxanide coated by one or more polymers of pH-dependent solubility. 2. A pharmaceutical composition according to claim 1, characterized in that the fraction of pH-dependent release begin to release nitazoxanide at a pH between 5.0 and 7.5. 3. A pharmaceutical composition according to claim 1 and 2, characterized in that the fraction of pH-dependent release is formed by two fractions, a fraction formed by coated granules that begin to release between pH 5.0 and pH 6.0 and a fraction formed by Coated granules that starts to release between pH 6.5 and 7.5. 4. A pharmaceutical composition according to claim 1 to 3, characterized in that the fraction of pH-dependent release is composed of two fractions, a fraction formed by coated granules that begin to release at pH 5.5 and a fraction formed by coated granules that they start releasing at pH 7.0. 5. A pharmaceutical composition according to claims 1 to 4, characterized in that the granules are coated by one or more polymers of pH-dependent solubility selected from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate and methacrylic acid copolymers. 6. A pharmaceutical composition according to claims 1 to 5, characterized in that the granules are coated with methacrylic acid copolymers. 7. A pharmaceutical composition according to claims 1 to 6, characterized in that the granules that start to release at pH 5.5 are coated by methacrylic acid-ethylacrylate copolymer partially neutralized with sodium hydroxide, and the granules begin to release at pH 7.0 are coated with a mixture of methacrylic acid-methyl methacrylate copolymer and methacrylic acid methacrylate copolymer. 8. A pharmaceutical composition according to claims 1 to 7, characterized in that when measuring the solution of the nitazoxanide of said composition in a USP apparatus 2 (paddles), at 100 rpm in a medium of 1000 ml of 0.1 solution. N of hydrochloric acid with 6% cetyltrimethylammonium bromide, the percentage dissolved is between 25 and 55% 60 minutes after the start of the test. 9. A pharmaceutical composition according to claims 1 to 8, characterized in that when the solution of the nitazoxanide of said composition is measured in an apparatus 2 of the USP (pallets), at 100 rpm in a medium of 1000 ml of 0.1 solution. N hydrochloric acid with 6% cetyltrimethylammonium bromide for 60 minutes and an additional 60 minutes in a pH 5.5 phosphate buffer medium with 6% cetyltrimethylammonium bromide, the percentage dissolved is between 55% and 85%. 10. A pharmaceutical composition according to claims 1 to 9, characterized because the coated granules have a particle size of less than 850 microns. 11. A pharmaceutical composition according to claims 1 to 10, characterized in that it is packaged in single-dose sachets containing 200 to 3000 mg of nitazoxanide. 12. A pharmaceutical composition according to claims 1 to 10, characterized in that it is packaged in bottles containing 600 to 3000 mg of nitazoxanide. The process for preparing a pharmaceutical composition for oral administration in the form of granules for suspension of nitazoxanide according to claims 1 to 11, comprising (a) making an immediate release fraction composed of uncoated granules or powder without granulation of nitazoxanide, (b) making a pH-dependent release fraction and (c) mixing both fractions, characterized in that the preparation of the pH-dependent fraction comprises the steps of (1) preparing in a reactor an aqueous dispersion of nitazoxanide less than 100. microns and a binding agent, (2) atomizing the dispersion of nitazoxanide and binder obtained in step (1) onto inert cores of size less than 700 microns in a fluid bed equipment, (3) preparing an aqueous dispersion or a solution organic containing at least one polymer of pH-dependent solubility and a plasticizing agent and (4) coating in a fluid bed equipment. granules obtained in step (2) with the dispersion obtained in step (3). 14. The process for preparing a pharmaceutical composition for oral administration in the form of granules for suspension of nitazoxanide according to claim 12, further characterized in that the inert nuclei to be atomized the dispersion of nitazoxanide and binder obtained in step (1) have a size between 150 to 700 microns.